Evolutionary interactions between microbial pathogens and their hosts can mean the difference between a deadly pandemic and minor infection. The sequestration of iron and other micronutrients has recently emerged as a potent form of innate host defense termed nutritional immunity, which is actively counteracted by pathogen iron piracy to scavenge this nutrient from host proteins. While the molecular basis for these interactions have been established, the evolutionary implications of the battle for iron have not been previously investigated. I recently discovered that the primate iron transport protein transferrin has been engaged in a long- standing evolutionary conflict with TbpA, a bacterial surface receptor that targets transferrin as a nutrient iron source. Experimental evidence further indicates that transferrin evolution has played an important role during 40 million years of primate divergence and even in modern human populations. This proposal aims to complement my past training in biochemistry and evolutionary genetics with microbiology and genomic approaches to investigate mechanisms of bacterial pathogen evolution, using the transferrin-TbpA interface as a model system. During the K99 phase of this award I will investigate the functional consequences for rapid evolution in bacterial TbpA using molecular genetics as well as bacterial competition assays. This work will complement experimental evolution approaches using the transferrin-TbpA interface to study evolutionary trade-offs and pathogen host-range, work which I will carry forward into the independent R00 stage of the award. Together this proposal will lay the groundwork for an independent research program that integrates evolutionary genetics, biochemistry and microbiology to investigate the implications of host-pathogen evolution on human health and disease susceptibility.